Aralkylaminoethanol heterocyclic compounds

ABSTRACT

Heterocyclic aminoethanols of the formula 
     
         Het--CHOH--CH.sub.2 --NH--aralkyl 
    
     where het is a 6-10 membered N heterocycle are disclosed. The compounds are useful as pharmaceuticals for reducing intraocular pressure, for use as α- and β-and adrenergic blocking agents, as antihypertensive agents and for effecting bronchodilation.

This is a division of application Ser. No. 219,725 filed on Dec. 23,1980, now U.S. Pat. No. 4,358,455, issued Nov. 9, 1982.

BACKGROUND OF THE INVENTION

The present invention is concerned with heterocyclic compounds of theformula Het--CHOH--CH₂ --NH--aralkyl.

Substituted phenylaminoethanols of the formula Ph--CHOH--CH₂--NH--aralkyl where Ph is a substituted phenolic group are disclosed inU.S. Pat. No. 3,644,353; U.S. Pat. No. 3,705,233. These compounds haverandom activity as β-adrenergic stimulants and β-adrenergic blockers.These compounds are taught to be useful as pharmaceuticals for treatingglaucoma and cardiovascular disorders such as hypertension andarrhythmias.

Heterocyclic aminoethanols which have pharmaceutical utility have beendiscovered.

SUMMARY OF THE INVENTION

Heterocyclic compounds of the formula Het--CHOH--CH₂ --NH--aralkyl whereHet is 6-10-membered N-heterocyclic and their use as pharmaceuticals.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

An embodiment of the present invention is compounds of the formula

    Het--R                                                     I

and pharmaceutically acceptable salts thereof where Het is ##STR1##tautomers thereof, and pharmaceutically acceptable salts thereof wherein

R₁ is H or OH,

Z is O or NH,

R is ##STR2## wherein

R₃ is ##STR3## wherein

R₄ and R₅ are independently selected from H and C₁ -C₃ alkyl,

Y is CH₂, (CH₂)₂, (CH₂)₃, (CH₂)₄ or --CH₂ O--

R₆ is H, OH, O--C₁ -C₃ alkyl, methylenedioxy halogen or C₁ -C₃ alkyl and

n is 1 or 2.

The pharmaceutically acceptable salts are the salts of the Formula Ibase with suitable organic or inorganic acids. Suitable organic acidsinclude carboxylic acids such as acetic acid, pamoic acid, pivalic acid,oxalic acid, lauric acid, pelargonic acid, citric acid, tartaric acid,maleic acid, oleic acid, propanoic acid, succinic acid, isobutyric acid,malic acid and the like, the non-carboxylic acids such as isethionicacid and methane sulfonic acid. Maleic acid salts are preferred.Suitable inorganic acids are the hydrogen halides e.g. HCl, HI, HBr,phosphoric acid and sulfuric acid. The hydrohalide salts, and especiallythe hydrochlorides, are preferred. These salts can be prepared bytreating the free base with an appropriate amount of a suitable acid,generally in a solvent.

R₃ is the phenalkyl group ##STR4## Each of R₄ and R₅ may be C₁ -C₃ alkyle.g. CH₃, C₃ H₇, C₂ H₅ and the like or hydrogen. CH₃ and H are preferredR₄ /R₅ substituents while it is more preferred when one or both of R₄/R₅ is CH₃. Y is CH₂ O, CH₂ or (CH₂)₁₋₄, with CH₂ and (CH₂)₂ beingpreferred. R₆ is H, OH, O--C₁ -C₃ alkyl, halogen (Br, Cl, I or F with Brand Cl being preferred), methylenedioxy or C₁ -C₃ --alkyl, branched orlinear. H and OCH₃ are preferred definitions of R₆.

Examples illustrating useful R₃ groups are ##STR5## and the like.

Of the heterocyclic groups, the (a), (b), (c), (e), (g) and (h) groupsare preferred; the (a), (b), (c), (e) and (g) groups are more preferred;the (a), (b), (e) and (g) groups are especially preferred. The (b), (e)or (g) groups are more particularly preferred.

The monocyclic group ##STR6## and the bicyclic group ##STR7## are mostpreferred. In the heterocyclic groups tautomers occur and are included.An illustrative example of such tautomers is ##STR8##

The compounds of formula I have one chiral center at the 1-position inthe aminoethanol substituent and can have a second chiral center whenthe R₄ and R₅ substituents in the R₃ group are different. The chiralcenters confer optical activity on the formula I compounds.

All the optical isomer forms, that is mixtures of enantiomers ordiastereomers, e.g. racemates as well as individual enantiomers ordiasteriomers of formula I are included. These individual enantiomersare commonly designated according to the optical rotation they effect bythe symbols (+) and (-), (L) and (D), (l) and (d) or combinationsthereof. These isomers may also be designated according to theirabsolute spatial configuration by (S) and (R), which stands for sinisterand rectus, respectively.

The individual optical isomers may be prepared using conventionalresolution procedures, e.g., treatment with an appropriate opticallyactive acid, separating the diasteriomers and then recovering thedesired isomer.

A compound of Formula I is useful for treating glaucoma since itdecreases intraocular pressure when topically administered to the eye.The ability to lower intraocular pressure is determined using an in-vivoprotocol in a rabbit model.

Said compound is preferably administered in the form of an opthalmicpharmaceutical composition adapted for topical administration to the eyesuch as a solution, an ointment or as a solid insert. Formulations ofthe compound may contain from 0.01 to 5% and especially 0.5 to 2% ofmedicament. Higher dosages as, for example, about 10% or lower dosagescan be employed provided the dose is effective in lowering intraocularpressure. As a unit dosage form, between 0.001 to 5.0 mg., preferably0.005 to 2.0 mg., and especially 0.005 to 1.0 mg. of the compound isgenerally applied to the human eye.

The pharmaceutical composition which contains the compound may beconveniently admixed with a non-toxic pharmaceutical organic carrier, orwith a non-toxic pharmaceutical inorganic carrier. Typical ofpharmaceutically acceptable carriers are, for example, water, mixturesof water and water-miscible solvents such as lower alkanols oraralkanols; vegetable oils; polyalkylene glycols; petroleum based jelly;ethyl cellulose; ethyl oleate; carboxymethylcellulose;polyvinylpyrrolidone; isopropyl myristate, and other conventionallyemployed acceptable carriers. The pharmaceutical preparation may alsocontain non-toxic auxiliary substances such as emulsifying, preserving,wetting agents, bodying agents and the like, as for example,polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500,4,000, 6,000 and 10,000 bacterial components such as quaternary ammoniumcompounds, phenylmercuric salts known to have cold sterilizingproperties and which are non-injurious in use, thimerosal, methyl andpropyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredientssuch as sodium chloride, sodium borate, sodium acetate, glyconatebuffers, and other conventional ingredients such as sorbitanmonolaurate, triethanolamine, oleate, polyoxyethylene sorbitanmonopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol,thiosorbitol, ethylenediamine tetracetic acid, and the like.Additionally, suitable ophthalmic vehicles can be used as carrier mediafor the present purpose including conventional phosphate buffer vehiclesystems, isotonic boric acid vehicles, isotonic sodium chloridevehicles, isotonic sodium borate vehicles and the like. Thepharmaceutical preparation may also be in the form of a solid insert.For example, one may use a solid water soluble polymer as the carrierfor the medicament. The polymer used to form the insert may be any watersoluble non-toxic polymer, for example, cellulose derivatives such asmethylcellulose, sodium carboxymethyl cellulose, (hydroxyloweralkylcellulose), hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose; acrylates and as polyacrylic acid salts;natural products such as gelatin, alginates, pectins, tragacanth,karaya, chondrus, agar, acacid; the starch derivatives such as starchacetate, hydroxyethyl starch ethers, hydroxypropyl starch, as well asother synthetic derivatives such as poly vinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralizedcarbopol and xanthan gum, and mixtures of said polymer.

Preferably the solid insert is prepared from cellulose derivatives suchas methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose orhydroxypropylmethyl cellulose or from other synthetic materials such aspolyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide orpolyvinyl methylether. Hydroxypropyl cellulose, one of the preferredpolymers for the preparation of the insert is available in severalpolymeric forms, all of which are suitable in the preparation of theseinserts. Thus, the product sold by Hercules, Inc. of Wilmington, Del.under the name KLUCEL such as KLUCEL HF, HWF, MF, GF, JF, LF and EFwhich are intended for food or pharmaceutical use are particularlyuseful. The molecular weight of these polymers useful for the purposesdescribed herein may be at least 30,000 to about 1,000,000 or more.Similarly, an ethylene oxide polymer having a molecular weight of up to5,000,000 or greater, and preferably 100,000 to 5,000,000 can beemployed. Further, for example, POLYOX a polymer supplied by UnionCarbide Co. may be used having a molecular weight of about 50,000 to5,000,000 or more and preferably 3,000,000 to 4,000,000. Other specificpolymers which are useful are polyvinyl pyrrolidine having a molecularweight of from about 10,000 to about 1,000,000 or more, preferably up toabout 350,000 and especially about 20,000 to 60,000; polyvinyl alcoholhaving a molecular weight of from about 30,000 to 1,000,000 or moreparticularly about 400,000 and especially from about 100,000 to about200,000; hydroxypropylmethyl cellulose having a molecular weight of fromabout 10,000 to 1,000,000 or more, particularly up to about 200,000 andespecially about 80,000 to about 125,000; methyl cellulose having amolecular weight of from about 10,000 to about 1,000,000 or more,preferably up to about 200,000 and especially about 50 to 100,000; andCARBOPOL (carboxyvinyl polymer) of B. F. Goodrich and Co. designated asgrades 934, 940 and 941. It is clear that for the purpose of thisinvention the type and molecular weight of the polymer is not critical.Any water soluble polymers can be used having an average molecularweight which will afford dissolution of the polymer and accordingly themedicament in any desired length of time. The inserts, therefore, can beprepared to allow for retention and accordingly effectiveness in the eyefor any desired period. The insert can be in the form of a square,rectangle, oval, circle, doughnut, semi-circle, 1/4 moon shape, and thelike. Preferably the insert is in the form of a rod, doughnut, oval or1/4 moon. The insert can be readily prepared, for example, by dissolvingthe medicament and the polymer in a suitable solvent and the solutionevaporated to afford a thin film of the polymer which can then besubdivided to prepare inserts of appropriate size. Alternatively theinsert can be prepared by warming the polymer and the medicament and theresulting mixture molded to form a thin film. Preferably, the insertsare prepared by molding or extrusion procedures well known in the art.The molded or extruded product can then be subdivided to afford insertsof suitable size for administration in the eye.

The insert can be of any suitable size to readily fit into the eye. Forexample, castings or compression molded films having a thickness ofabout 0.25 mm. to 15.0 mm. can be subdivided to obtain suitable inserts.Rectangular segments of the cast or compressed film having a thicknessbetween about 0.5 and 1.5 mm can be cut to afford shapes such asrectangular plates of 4×5-20 mm or ovals of comparable size. Similarly,extruded rods having a diameter between about 0.5 and 1.5 mm, can be cutinto suitable sections to provide the desired amount of polymer. Forexample, rods of 1.0 to 1.5 mm. in diameter and about 20 mm. long arefound to be satisfactory. The inserts may also be directly formed byinjection molding. It is preferred that the ophthalmic insertscontaining the medicament of the present invention be formed so thatthey are smooth and do not have any sharp edges or corners which couldcause damage to the eye. Since the terms smooth and sharp edges orcorners are subjective terms, in this application these terms are usedto indicate that excessive irritation of the eye will not result fromthe use of the insert.

The ocular medicinal inserts can also contain plasticizers, bufferingagents and preservatives. Plasticizers suitable for this purpose must,of course, also be completely soluble in the lacrimal fluids of the eye.Examples of suitable plasticizers that might be mentioned are water,polyethylene glycol, propylene glycol, glycerine, trimethylol propane,di and tripropylene glycol, hydroxypropyl sucrose and the like.Typically, such plasticizers can be present in the ophthalmic insert inan amount ranging from up to 1 about 30% by weight. A particularlypreferred plasticizer is water which is present in amounts of at leastabout 5% up to about 40%. In actual practice, a water content of fromabout 10% to about 20% is preferred since it may be easily accomplishedand adds the desired softness and pliability to the insert.

When plasticizing the solid medicinal product with water, the product iscontacted with air having a relative humidity of at least 40% until saidproduct picks up at least about 5% water and becomes softer and morepliable. In a preferred embodiment, the relative humidity of the air isfrom about 60% to about 99% and the contacting is continued until thewater is present in the product in amounts of from about 10% to about20%.

Suitable water soluble preservatives which may be employed in the insertare sodium bisulfate, sodium thiosulfate, ascorbate, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate,phenylmercuric borate, parabens, benzyl alcohol and phenylethanol. Theseagents may be present in amounts of from 0.001 to 5% by weight of solidinsert, and preferably 0.1 to 2%.

Suitable water soluble buffering agents are alkali, alkali earthcarbonates, phosphates, bicarbonates, citrates, borates and the like,such as sodium phosphate, citrate, borate, acetate, bicarbonate andcarbonate. These agents may be present in amounts sufficient to obtain apH of the system of between 5.5 to 8.0 and especially 7-8; usually up toabout 2% by weight of polymer. The insert may contain from about 1 mg.to 100 mg. of water soluble polymer, more particularly from 5 to 50 mg.and especially from 5 to 20 mg. The medicament is present from about 0.1to about 25% by weight of insert.

The ability of the Formula I compound to lower intraocular pressure isdetermined in rabbits with experimental glaucoma induced by intraocularinjection of α-chymotrypsin. Compounds of Formula I are effective inlowering intraocular pressure after topical application. Pressure isreduced in the normal and the glaucomatous eye.

The compounds (Formula I) of the present invention have β-adrenergicblocking activity. This β-adrenergic blocking activity is determined bymeasuring the ability of representative compounds to block theβ-adrenergic stimulant effect of isoproterenol in a test animal.

The compounds of the present invention also have α-adrenergic blockingactivity. This α-adrenergic blocking activity is determined, (a) invitro by measuring the ability of a representative Formula I compound todisplace radio labeled α-adrenergic antagonist from a tissue substrateor (b) in vivo, by measuring the ability of a representative Formula Icompound to block the α-adrenergic stimulant effect of phenylephrine inanesthetized normotensive animals.

The present compounds exhibit antihypertensive activity of immediateonset. This rapid onset antihypertensive activity is determined byadministering a representative compound of the present invention tospontaneously hypertensive (SH) rats and measuring the effect on bloodpressure.

The α- and β-adrenergic blocking activity of the present compoundsindicates that the compounds may be useful in humans for treatingcardiovascular conditions susceptible to β-blockade therapy (e.g.,angina pectoris, arrhythmia) while minimizing bronchoconstriction viaα-adrenergic blockade. This α/β-blocking effect can be useful intreating hypertension caused by pheochromocytoma.

For use as α/β-adrenergic blocking agents, and/or antihypertensiveagents the compounds of the present invention can be administeredorally, by inhalation, by suppository or parenterally, i.e.,intravenously, intraperitoneally, etc. and in any suitable dosage form.The compounds may be offered in a form (1) for oral administration,e.g., as tablets in combination with other compounding ingredients(diluents or carriers) customarily used such as talc, vegetable oils,polyols, benzyl alcohols, starches, gelatin and the like--or dissolved,dispersed or emulsified in a suitable liquid carrier--or in capsules orencapsulated in a suitable encapsulating material, or (2) for parenteraladministration, dissolved, dispersed, or emulsified in a suitable liquidcarrier or diluent or (3) as an aerosol or (4) as a suppository. Theratio of active ingredient (present compound) to compounding ingredientswill vary as the dosage form required. Conventional procedures are usedto prepare the pharmaceutical formulations. The effective daily dosagelevel for the present compounds for applications other than treatment ofthe eye may be varied from about 10 mg. to about 3000 mg. Daily dosesranging from about 100 to about 2500 mg. are preferred, with about 200to about 1000 mg. being a more preferred range. Oral administration ispreferred. Either single or multiple daily doses may be administereddepending on unit dosage.

Compounds of formula I also have bronchodilator activity. This isdetermined by measuring the effectiveness of the compound to antagonizeslow reacting substance of anaphylaxis (SRS-A). The compounds are thususeful to treat conditions in mammals especially human beings whichbenefit from bronchodilation such as asthma, etc. For use as abronchodilator, the compound is administered orally or parenterally inconventional dosage form such as tablet, capsule, solution, dispersion,emulsion and the like. The compound may also be administered as a sprayor an aerosol using an appropriate delivery device and formulation. Theoral route is preferred. Sufficient formula I compound is administeredto produce the desired level of bronchodilation. Daily dosages for oralor parenteral administration may range from about 1 mg. to about 300 mg,and preferably from about 2 to about 150 mg. Spray or aerosol deliverywill be in metered doses ranging from about 50 to about 1000 mcg,administered as needed.

Thus, other embodiments of the present invention are the pharmaceuticalcompositions containing a therapeutically effective amount of theFormula I compound and methods for (1) treating hypertension, othercardiovascular conditions, or glaucoma, (2) for lowering intraocularpressure, or (3) for effecting bronchodilation.

Compounds of formula I may be prepared by any convenient process. Onesuch useful process is illustrated by the following set of reactionequations: ##STR9## Het' is a heterocyclic group (a), (b), (c) or asuitable precursor thereof.

Another process for preparing some compounds of formula I is illustratedby the following set of reaction equations: ##STR10##

The N-oxide for the formula II compound is prepared as illustrated bythe following set of reaction equations: ##STR11##

Another process for preparing some compounds of formula I is illustratedby the following set of reaction equations: ##STR12##

The following examples illustrate preparation of representativecompounds of formula I. The processes used are those set out in the setsof equations set out above. All temperatures are in degrees Celsius.

EXAMPLE 1

Preparation of7-[1-hydroxy-2-(4-phenyl-2-butylamino)ethyl]-2H-1,4-benzoxazin-3(4H)-onemaleate salt of the formula: ##STR13##

A. 7-Acetyl-2H-1,4-benzoxazin-3(4H)-one (A) ##STR14##

To a stirred mixture of 17.7 gm. (0.117 moles) of4-amino-3-hydroxyacetophenone (Eur. J. Med. Chem., 9, 491 (1974) and35.4 gm. (0.42 moles) of NaHCO₃ in a mixture of 350 ml. of water and 350ml. of 2-butanone was added 14 ml. (0.176 moles) of chloroacetylchloride over 30 min. at 25° C. The reaction mixture was then stirredand heated at 90° C. for 5 hours, after which a further 1 ml. (0.013moles) of chloroacetyl chloride was added and heating continued for 2hours. TLC indicated no starting material remained. The reaction mixturewas cooled and poured into 1500 ml. of water. After stirring for 1 hour,the precipitate was filtered and air dried to yield 16.3 gm. of A, m.p.197°-198°. Extraction of the aqueous with ethyl acetate yielded afurther 4.5 gm. of A; total yield, 93%.

B. 7-Bromoacetyl-2H-1,4-benzoxazin-3(4H)-one (B) ##STR15##

A mixture 4 gm. (20.9 mmoles) of 7-acetyl-2H-1,4-benzoxazin-3(4H)-oneand 8.9 gm. (39.9 mmoles) of finely ground cupric bromide in 1000 ml. ofethyl acetate was stirred and refluxed for 18 hours. A further 3.6 gm.(16 mmoles) of cupric bromide was added and reflux continued for 6hours. The reaction mixture was filtered, decolorized with charcoal andupon concentration there was obtained 3.8 gm. (68% yield) of B, m.p.217°-219° (dec.)

C. 7-Azidoacetyl-2H-1,4-benzoxazin-3(4H)-one (C) ##STR16##

To a suspension of 270 mg. (1 mmole) of7-bromoacetyl-2H-1,4-benzoxazin-3(4H)-one in 20 ml. of methanol wasadded a solution of 78 mg. (1.2 mmoles) of sodium azide in 2 ml. ofwater adjusted to pH 5 with acetic acid. After stirring for 20 hours at25° C., the precipitate was filtered off, rinsed with water and airdried to give 137 mg. (59% yield) of C, m.p. 180° C. (dec.)

D. 7-(1-hydroxy-2-azidoethyl)-2H-1,4-benzoxazin-3(4H)-one (D) ##STR17##

To solution of 5.6 gm. (24.1 mmoles) of7-azidoacetyl-2H-1,4-benzoxazin-3(4H)-one in 750 ml. of methanol at 50°C. was added 4.56 gm. (120 mmoles) of sodium borohydride was added inportions (vigorous gas evolution). After addition was complete, thereaction was stirred for 1 hour, 50 ml. of water and 1.5 ml. of aceticadded and the mixture evaporated to dryness. Three one hundredmilliliter portions of methanol were evaporated from the residue, whichwas then treated with 200 ml. of water. After adjusting of the pH to 5with acetic acid, the aqueous suspension was extracted with 3×200 ml. ofethyl acetate. The combined organic extracts were washed with 0.5Nacetic acid, 5% NaHCO₃, dried (Na₂ SO₄) and evaporated. Trituration ofthe residue with 50 ml. of ether and filtration gave 4.5 gm. (80% yieldof D, m.p. 121°-123° C. (dec.)

E. 7-(1-hydroxy-2-aminoethyl)-2H-1,4-benzoxazin-3(4H)-one hydrochloride##STR18##

A solution of 4.5 gm. (19.2 mmoles) of D in 120 ml. of methanolcontaining 1 ml. of 12N HCl was hydrogenated over 10% Pd/C in a Parrapparatus at 25° C. and 50 p.s.i. for 18 hours. Filtration andevaporation left 4.5 gm. of crude E, which was combined with the crudeproduct from a second hydrogenation of 5.0 gm. of D to give 10.2 gm. ofcrude E. The free base of E was obtained by passage of an aqueoussolution (100 ml.) of crude E through 130 ml. of AG-50W-X8 cationexchange resin (100-200 mesh) in the acid form, followed by elution with1.5N NH₄ OH. Evaporation yielded 5.2 gm. of crude E as the free base,which upon crystallization from 300 ml. of ethanol gave 3.62 gm.containing one-fourth of a mole of water: m.p. 179°-182° C.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    56.47         5.88   13.18                                           Found    56.26         5.83   13.17                                           ______________________________________                                    

The hydrochloride (E) was prepared in ethanol and after tworecrystallizations had m.p. 228° C. (dec.).

    ______________________________________                                        Anal.      C      H           N    Cl                                         ______________________________________                                        Calc.      49.09  5.35        11.45                                                                              14.49                                      Found      49.19  5.63        11.32                                                                              14.31                                      ______________________________________                                    

F.7-[1-hydroxy-2-(4-phenyl-2-butylamine)ethyl]-2H-1,4-benzoxazin-3(4H)-onemaleate salt (F) ##STR19##

To a solution of 2.3 gm. (11 mmoles) of E free base and 1.5 gm. (6mmoles) of E in 100 ml. of methanol were added 2.5 gm. (17 mmoles) of4-phenyl-2-butanone and 1.07 gm. (17 mmoles) of sodium cyanoborohydrideand the mixture stirred in the presence of 4A molecular sieves at 25° C.for 18 hours. TLC showed no starting materials present and one principalnew product. The reaction mixture was acidified with 12N HCl, stirredfor 20 min., filtered, and evaporated and the residue slurried withether. The insoluble hygroscopic solid was separated by filtration,suspended in 100 ml. of IN NaHCO₃, and the mixture extracted with 3×100ml. of ethyl acetate. The combined organic extracts were washed withwater, dried and evaporated to leave 4.2 gm. of solid crude F free base.This was slurried four times with 20 ml. of ether to give 2.85 gm. ofpurified free base. To a hot solution of the free base in ethyl acetatewas added a hot solution of 0.97 gm. (8.38 mmoles) of maleic acid in aminimum of ethyl acetate (total volume was 200 ml). Upon seeding andcooling, there was obtained 3.6 gm. of crude F. This was recrystallizedfrom 250 ml. of hot acetonitrile by addition of ether to turbidity andcooling to give 2.6 gm. (5.7 mmoles, 34 % yield) of F, m.p. 132°-137° C.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    63.14         6.18   6.14                                            Found    63.33         6.32   6.13                                            ______________________________________                                    

EXAMPLE 2

Preparation of6-[1-hydroxy-2-(4-phenyl-2-butylamino)ethyl]-2H-1,4-benzoxazin-3(4H)-onemaleate salt of the formula: ##STR20##

Starting with 6-chloroacety-2H-1,4-benzoxazin-3(4)-one, (C.R. Acad.Sci., C, 270, 1601 (1970), and following essentially the procedures ofExample 1, steps C, D, E and F there were obtained successively:

A 6-Azidoacetyl-2H-1,4-benzoxazin-3(4H)-one ##STR21##

m.p. 177°-178° C. (dec.) 85% yield:

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    51.72         3.47   24.13                                           Found    51.55         3.48   23.90                                           ______________________________________                                    

B 6-(1-hydroxy-2-azidoethyl)-2H-1,4-benzoxazin-3(4H)-one ##STR22##

m.p. 137°-138° C., 79% yield.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    51.28         4.30   23.92                                           Found    51.37         4.35   24.07                                           ______________________________________                                    

C 6-(1-hydroxy-2-aminoethyl)-2H-1,4-benzoxazin-3(4H)-one ##STR23##

m.p. 175°-178° C., 78% yield.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    57.68         5.81   13.46                                           Found    57.50         5.91   13.30                                           ______________________________________                                    

D6-[1-hydroxy-2-(4-phenyl-2-butylamino)ethyl]-2H-1,4-benzoxazin-3(4)-onemaleate salt ##STR24##

Free base: m.p. 125°-130° C., 83% yield.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    70.56         7.11   8.23                                            Found    70.57         7.40   8.33                                            ______________________________________                                    

Maleate: m.p. 154°-157° C., 96% yield.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    63.14         6.18   6.14                                            Found    63.25         6.19   6.20                                            ______________________________________                                    

EXAMPLE 3

Preparation of2,3-dihydro-α-{[(1-methyl-3-phenylpropyl)amino]methyl}-2-oxo-6-benzoxazolemethanolmaleate salt of the formula: ##STR25##

Starting with 6-chloroacetyl-2,3-dihydro-2-oxobenzoxazole (Eur. J. Med.Chem., 9, 491 (1974), and following essentially the procedures ofExample 1, steps C, D, E and F, there were obtained successively:

A. 6-Azidoacetyl-2,3-dihydro-2-oxobenzoxazole ##STR26##

m.p. 250° C. (dec.), 78% yield.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    49.55         2.77   25.68                                           Found    49.71         2.90   24.14                                           ______________________________________                                    

B 2,3-Dihydro-α-(azidomethyl)-2-oxo-6-benzoxazolemethanol ##STR27##

m.p. 119°-121.5° C., 78% yield.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    49.09         3.66   25.44                                           Found    49.01         3.76   23.47                                           ______________________________________                                    

C 2,3-Dihydro-α-(aminomethyl)-2-oxo-6-benzoxazolemethanol.HCl ##STR28##

m.p. 315° C., (dec.) 60% yield.

    ______________________________________                                        Anal.      C      H           N    Cl                                         ______________________________________                                        Calc.      46.86  4.81        12.14                                                                              15.37                                      Found      47.10  4.89        11.75                                                                              15.15                                      ______________________________________                                         2,3-Dihydro-α{[(1-methyl-3-phenylpropyl)amino]methyl}-2-oxo-6-benzox    azolemethanol maleate salt     ##STR29##

m.p. 163°-165° C., 31% yield.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    62.43         5.92   6.33                                            Found    62.75         6.03   6.34                                            ______________________________________                                    

EXAMPLE 4

Preparation of6-amino-α-{[(1-methyl-3-phenylpropyl)amino]methyl]}-3-pyridinemethanoldihydrochloride salt of formula: ##STR30##

A. 6-Acetyl tetrazolo[1,5-a]pyridine (A) ##STR31##

To a stirred solution of 8.4 gm. (51.6 mmoles) of2-chloro-5-acetylpyridine and 8.4 gm. (129 mmoles) of sodium azide in150 ml. of ethanol and 150 ml. of water was added 75 ml. of 10% HCl overa period of 20 min. The reaction mixture was then heated to reflux for18 hours, cooled in an ice bath and the resulting crystals filtered offto give a first crop of 6.0 gm. A second crop of 1.0 gm. was obtainedfor a total of 7.0 gm. of A, (84.% yield), m.p. 159°-160° C.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    51.85         3.73   34.56                                           Found    52.01         3.91   34.40                                           ______________________________________                                    

B. 6-Bromoacetyltetrazolo[1,5-a]pyridine (B) ##STR32##

To a partial solution of 55.4 gm. (0.34 moles) of A in 1500 ml. ofglacial acetic acid, saturated with HBr, and cooled in an ice bath wasadded a solution of 57 gm. (0.32 moles) of bromine in 500 ml. of glacialacetic acid over a period of 2 hours. The reaction was evaporated todryness and the residue taken up in ethyl acetate. A small amount ofinsoluble material was filtered off and the ethyl acetate was washedwith water, IN NaHCO₃ solution and dried (Na₂ SO₄). Evaporation left82.4 gm. of crude product which contained 80% of B. A portion (71 gm.)of the crude material was slurried twice with 500 ml. of 10% ethylacetate in ether to give 56 gm. of B, sufficiently pure for further use(79% yield). A sample recrystallized from ethanol had m.p. 110°-113° C.

    ______________________________________                                        Anal.      C      H           N    Br                                         ______________________________________                                        Calc.      34.88  2.09        23.24                                                                              33.15                                      Found      35.05  2.12        23.14                                                                              33.36                                      ______________________________________                                    

C 2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane (C) ##STR33##

To a suspension of 37 gm. (154 mmoles) of B in 280 ml. of methanol wasadded 1.85 gm. (49 mmoles) of sodium borohydride with stirring at 20° C.over a period of 30 min. The reaction mixture was evaporated to drynessand agitated well with a mixture of 500 ml. of ethyl acetate and 500 ml.of 1N NaOH. The organic layer was separated, washed with water,decolorized with charcoal, dried and evaporated to leave an oily solid.This was chromatographed over silica gel using ethyl acetate. Thepartially purified material thus obtained as crystallized from 130 ml.of ethanol to give 18.2 gm. (73% yield), of C, m.p. 108°-110° C.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    51.85         3.75   34.56                                           Found    51.71         3.53   34.34                                           ______________________________________                                         α-[(1-methyl-3-phenylpropyl)amino]methyl-6-tetrazolo[1,5-a]pyridinem    ethanol (D)     ##STR34##

A solution 10 gm. (61.7 mmoles) of C and 10 gm. (67.1 mmoles) of4-phenyl-2-aminobutane in 50 ml. of ethanol was heated to reflux for 1.5hours. The reaction mixture was evaporated and the residue crystallizedfirst from a minimum of ethyl acetate and recrystallized from 100 ml. ofethanol to give 11.4 gm. of D. A second crop 2.3 gm. obtained bychromatography of the mother liquors to give a total of 13.7 gm. (71%yield) of D, m.p. 117°-120° C.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    65.57         6.80   22.48                                           Found    65.57         6.95   22.48                                           ______________________________________                                    

The maleate salt was prepared in ethylacetate:

m.p. 121°-124° C.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    59.00         5.90   16.39                                           Found    59.29         6.13   16.31                                           ______________________________________                                    

E 6-Amino-α-[(1-methyl-3-phenylpropyl)amino]methyl-3-pyridinemethanoldihydrochloride (E) ##STR35##

A solution of 11 gm. (35.4 mmoles) of D and 24 gm. (106 mmoles) ofstannous chloride dihydrate in 60 ml. of 12N HCl is heated to reflux for2 hours. The reaction was evaporated to dryness, the residue suspendedin 150 ml. of methanol and basified with conc. NH₄ OH. The precipitatedsalts were removed by filtration and the product in the filtratechromatographed over 600 gm. of silica gel, eluting with a mixture ofCH₂ Cl₂ :CH₃ OH:conc. NH₄ OH(15:5:4), to give, upon evaporation of theeluate, 6.8 gm. (67% yield) of the free base of E.

The dihydrochloride salt was prepared from the free base in ethanol, byaddition of 12N HCl and cooling, in 65% yield.

m.p. 156°-158° C.

    ______________________________________                                        Anal.    C        H           N    Cl                                         ______________________________________                                        Calc.    56.98    7.03        11.73                                                                              19.79                                      Found    56.58    7.32        11.29                                                                              19.96                                      ______________________________________                                    

The product E is a racemic mixture of diastereomers containing the 4isomers S,S; S,R; R,S and R,R. By using a specific isomer of the aminereactant in step D., for example, S-4-phenyl-2-aminobutane, a mixture of2 isomers of E i.e. S,S-E free base and R,S-E free base, is obtained.This mixture is conventionally separated, for example, bychromatography, and the individual isomers i.e. S,S-E free base andR,S-E free base, are obtained. When R-4-phenyl-2-aminobutane is used,the corresponding S,R and R,R isomers of E free base are obtained. Thisprocedure for preparing individual isomers may be used for thepreparation of any Formula I compound which involves the reaction of anepoxide and an amine.

EXAMPLE 5

Preparation of6-amino-α-{[(1,1-dimethyl-3-phenylpropyl)amino]-methyl}-3-pyridinemethanoldihydrochloride hemihydrate: ##STR36##

Starting with 4-phenyl-2-amino-2-methylbutane and the product C ofExample IV, and following essentially the procedure of Example IV, stepsD and E, there was obtained successively:

A.α-{[(1,1-dimethyl-3-phenylpropyl)amino]methyl}-6-tetrazolo[1,5-a]-pyridinemethanol(A) ##STR37##

m.p. 126°-127° C., 76% yield.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    66.44         7.12   21.52                                           Found    66.70         7.20   21.37                                           ______________________________________                                    

The maleate salt was prepared in ethylacetate:

m.p. 167°-168° C., 98% yield.

    ______________________________________                                        Anal     C             H      N                                               ______________________________________                                        Calc.    59.85         6.16   15.86                                           Found    59.88         6.35   15.74                                           ______________________________________                                    

B.6-Amino-α-{[(1,1-dimethyl(-3-phenylpropyl)amino]methyl}-3-pyridinemethanoldihydrochloride hemihydrate ##STR38##

m.p. 185°-188° C. (dec.)., 54% yield.

    ______________________________________                                        Anal       C      H           N    Cl                                         ______________________________________                                        Calc       56.69  7.14        11.02                                                                              18.60                                      Found      56.96  7.18        11.04                                                                              18.54                                      ______________________________________                                    

EXAMPLE 6

Preparation of6-amino-α-{[1-methyl-3-phenylpropyl)amino]methyl}-3-pyridinemethanol-1-oxidedihydrochloride salt A ##STR39##

A solution of 2.0 gm. (7.02 mmoles) of the free base of the product ofstep E of Example 4 in a mixture of 20 ml. of pyridine and 10 ml. ofacetic anhydride was stirred at 20° C. for 18 hr. The excess reactantswere evaporated and the residue partitioned between 150 ml. of water and150 ml. of ethyl acetate. The organic layer was washed with 1N Na₂ CO₃solution, dried and evaporated to give 2.6 gm. (90% yield) of thetriacetylated intermediate.

The protected intermediate was dissolved in 30 ml. of chloroform and 1.4gm. (25% excess) of m-chloroperbenzoic acid was added. After stirringthe solution for 3 hr. at 20° C., 2 gm. of Ca(OH)₂ powder was added andstirring continued for 30 minutes. The reaction was filtered, thefiltrate evaporated and the residue (2.3 gm.) was chromatographed over400 gm. of silica gel eluting with 10% methanol in ethyl acetate. Twofractions were obtained: (a) 0.50 gm., a single diastereoisomer (b) 1.71gm. a 1:1 mixture of diastereoisomers (2.21 gm. 82% yield).

The material from fraction (b) was dissolved in 25 ml. of 6N HCl andheated to reflux for 3 hr., and the reaction mixture then evaporated todryness.

The residue was dissolved in methanol, basified with conc. NH₄ OH, andreevaporated to dryness. The residue, containing the free base, waschromatographed over 100 gm. of silica gel using methanol-methylenechloride-conc. NH₄ OH (20:80:3) as eluant. The fractions containing thedesired product were combined and treated with HCl in 10 ml.. ofethanol. Evaporation and trituration of the residue with ether gave 1.0gm. (67% yield) of A.

m.p. 203°-210° C. (dec), 49% overall yield.

    ______________________________________                                        Anal.      C      H           N    Cl                                         ______________________________________                                        Calc.      54.56  6.73        11.23                                                                              18.95                                      Found      54.46  6.93        11.10                                                                              18.95                                      ______________________________________                                    

EXAMPLE 7

Preparation of5-{1-hydroxy-2-[1]-methyl-3-phenylpropyl)-amino]ethyl}-2(1H)-pyridinonefumarate hydrate: ##STR40##

A. 5-Acetyl-2-fluoropyridine (A) ##STR41##

To suspension of 20 gm. (142 mmoles) of 2-fluoro-5-pyridinecarboxylicacid (J. Am. Chem. Soc., 71, 1125 (1949)) in 750 ml. of ether, stirredand cooled in ice, was added 225 ml. of 1.6M methyl lithium (360 mmoles)in ether over 1 hr. The reaction was stirred for an additional 2 hr.,then 300 ml. of ice water was added. The aqueous layer was washed with2×100 ml. fresh ether, acidified and extracted with ether to give 5.0gm. (25%) of unreacted starting acid.

The original ether solution was rinsed with water, dried and evaporatedto yield 12.2 gm. of crude crystalline A, containing about 15% of thecorresponding t-alcohol. Chromatography over silica gel, eluting with 5%ethyl acetate in methylene chloride gave 7.81 gm. (52% yield) of A. Asample crystallized from hexane had m.p. 43°-44° C.

    ______________________________________                                        Anal.      C      H           N    F                                          ______________________________________                                        Calc.      60.43  4.35        10.07                                                                              13.65                                      Found      60.17  4.33         9.97                                                                              12.96                                      ______________________________________                                    

B. 5-Bromoacetyl-2-fluoropyridine (B) ##STR42##

Starting with 14 gm. (100 mmoles) of A, and following the proceduredescribed in Example 4, Step B, there was obtained 18.6 gm. of crude B,which consists of 7% of A, 82% of B and 11% of dibromoketone. Thismaterial was used without further purification for the next step.

C. (2-fluoropyrid-5-yl)oxirance (C) ##STR43##

Starting with 18.6 gm. of crude B and following essentially theprocedure of Example 4, Step C, there was obtained 13.4 gm. of crude C,which was suitable for use in the next step without furtherpurification.

D.6-Fluoro-α-{[(1-methyl-3-phenylpropyl)amino]methyl}-3-pyridinemethanol(D) ##STR44##

Starting with 15 gm. of crude C (containing ca. 67% of epoxide) andfollowing essentially the procedure described in Example 4, Step D,there was obtained after chromatography, 10.04 gm. (48% yield) of D,m.p. 81°-86° C.

    ______________________________________                                        Anal.      C      H           N    F                                          ______________________________________                                        Calc.      70.81  7.34        9.71 6.59                                       Found      70.61  7.45        9.69 6.43                                       ______________________________________                                    

E. 5-{1-hydroxy-2[(1-methyl-3-phenylpropyl)amino]ethyl}-2(1H)-pyridinonefumarate hydrate (E) ##STR45##

A solution of 2.03 gm. (7.0 mmoles) of D in 25 ml of 2N HCl was heatedto reflux for 6 hr. The reaction mixture was evaporated to dryness,re-dissolved in water and basified with NaHCO₃. The resulting mixturewas evaporated to dryness, the residue exhaustively extracted with hotethyl acetate and, after drying, the ethyl acetate was evaporated toyield 1.9 gm. of an oil (the free base of E). A sample crystallized togive m.p. 85°-89° C.

The salt was prepared by adding a solution of fumaric acid (1.4 gm) inmethanol (15 ml) to the base (3.15 gm) dissolved in equal quantities ofacetonitrile and methanol (250 ml. total), and evaporating the solutionto about 50 ml volume. After 2 hr. there was obtained, upon filtrationof the resulting crystals, 3.7 gm (75% yield) of E, m.p. 185°-189° C.(dec.)

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    59.99         6.71   6.66                                            Found    59.49         6.33   6.41                                            ______________________________________                                    

EXAMPLE 8

Preparation of5-{1-hydroxy-2-[(1,1-dimethyl-3-phenylpropyl)-amino]ethyl}-2(1H)-pyridinonedihydrochloride ##STR46##

Starting with the epoxide C of Example 7, and reacting it with4-phenyl-2-amino-2-ethylbutane, and proceeding essentially according toExample 7, Steps D and E, there was obtained successively:

A.6-Fluoro-α-{[(1,1-dimethyl-3-phenylpropyl)amino]-methyl}-3-pyridinemethanol(A) ##STR47##

m.p. 116°-118° C. (48% yield.

    ______________________________________                                        Anal.      C      H           N    F                                          ______________________________________                                        Calc.      71.50  7.66        9.26 6.28                                       Found      71.46  7.74        9.08 6.04                                       ______________________________________                                    

B.5-{1-hydroxy-2[(1,1-dimethyl-3-phenylpropyl)amino]-ethyl}-2(1H)-pyridinonedihydrochloride ##STR48##

m.p. 179°-181° C., 65% yield.

    ______________________________________                                        Anal.      C      H           N    Cl                                         ______________________________________                                        Calc.      57.35  6.97        7.43 19.74                                      Found      56.91  6.94        7.73 19.93                                      ______________________________________                                    

EXAMPLE 9

Preparation of1-hydroxy-5-{(1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl}-2(1H)-pyridinonehydrochloride ##STR49##

A.6-Methoxy-α-{[(1-methyl-3-phenylpropyl)amino]methyl}-3-pyridinemethanol(A) ##STR50##

To a solution of 5.9 gm. (20.5 mmoles) of product D from Example 7 in200 ml methanol was added 2 ml of 12N HCl, and the reaction stirred at20° C. It was analyzed periodically by NMR and tlc, and additionalquantities of 12N HCl were added as follows until the reaction wascomplete: 6 days--2 ml, 11 days, 2 ml, 17 days--reaction complete. Themixture was evaporated to dryness, partitioned between 1N NaHCO₃ andethyl acetate, and the organic layer evaporated to give 4.8 gm (79%yield) of A, m.p. 80°-83° C., containing a small amount of thecorresponding pyridone.

B.6-Methoxy-α-{[(1-methyl-3-phenylpropyl)amino]methyl}-3-pyridinemethanol-1-oxide-O,N-diacetylderivative (B) ##STR51##

A solution of 4.6 (15.3 mmoles) of A in 250 ml of pyridine and 20 ml ofacetic anhydride was stirred at 20° C. for 18 hr. The reaction mixturewas then evaporated to dryness and the residue taken up in ethylacetate, washed with 1N NaHCO₃ and water, and evaporated. The residualoil (˜6.6 gm) was dissolved in 500 ml of chloroform and 6 gm (˜34mmoles) of meta-chloroperbenzoic acid was added with stirring at 20° C.After 4 days the reaction was complete and 5.3 gm of Ca(OH)₂ was addedto the mixture. After 30 min., the reaction was filtered and evaporatedto leave 8 gm of an oil, which was chromatographed over silica gel using10% methanol in methylene chloride as elutant. There was recovered about2.7 gm (45%) of the unoxidized O,N-diacetyl derivative followed by 0.4gm (6.5%) of a single isomer of B, m.p. 139°-140° C.

    ______________________________________                                        Anal.    C             H      N                                               ______________________________________                                        Calc.    65.98         7.05   6.99                                            Found    66.00         7.18   7.03                                            ______________________________________                                    

Continued elution gave 2.1 gm (34% yield) of B as an oily mixture ofdiastereoisomers, used as such for the subsequent step.

C.1-Hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]ethyl}-2(1H)-pyridinonehydrochloride (C) ##STR52##

A solution of 2.6 gm (6.5 mmoles) of B in 100 ml of 2N HCl was heated toreflux for 20 hr.; analysis by NMR showed hydrolysis and cleavage to becomplete. The solution was treated with charcoal, extracted with ether,and evaporated to dryness to give a very hygroscopic solid. It wasdissolved in methanol-water and neutralized with conc. NH₄ OH. Thesolution of free base was absorbed onto an ion exchange column(AG50W-X8, 100-200 mesh, H⁺ form), and then eluted with 5% NH₄ OH.Evaporation of the eluate 1.8 gm of crude C as the free base.

Evaporation of 1.5 gm of C free base and 0.265 gm of NH₄ Cl dissolved in50 ml of methanol yielded the hydrochloride salt. The residue wasslurried in 25 ml of acetonitrile for 3 days, filtered and air dried togive 1.3 gm (58% yield) of C, m.p. 188° C. (dec.).

Claims to the invention follow:

What is claimed is:
 1. Compounds of the formula: ##STR53## tautomers,pharmaceutically acceptable salts and individual enantiomers thereofwherein ##STR54## wherein ##STR55## wherein R₄ and R₅ are independentlyselected from H and C₁ -C₃ alkyl,Y is CH₂, (CH₂)₂, (CH₂)₃, (CH₂)₄ or--CH₂ --O-- R₆ is H, OH, OCH₃, halogen, methylenedioxy or C₁ -C₃ alkyland n is 1 or 2; provided that when R₆ is methylenedioxy n is
 2. 2. Thecompounds of claim 1 wherein R₆ is H, OH or OCH₃.
 3. The compounds ofclaim 2 wherein Y is CH₂ O.
 4. The compounds of claim 2 wherein Y is CH₂or (CH₂)₂.
 5. The compounds of claim 4 wherein Y is (CH₂)₂.
 6. Thecompounds of claim 5 wherein R₃ is ##STR56## wherein R₄, and R₅, areeither CH₃ or H.
 7. The compounds of claim 6 wherein R₄ is H.
 8. Thecompounds of claim 6 wherein R₃ is ##STR57##
 9. A compound of claim 1having the formula: ##STR58## their maleate or HCl salts, individualenantiomers and tautomers.
 10. A pharmaceutical composition comprising apharmaceutically effective amount of a compound of claim 1 and an inertnon-toxic pharmaceutically acceptable carrier therefor.
 11. A method forreducing intraocular eye pressure by administering a pharmaceuticallyeffective intraocular eye pressure reducing amount of a composition ofclaim 10 in a suitable dosage form to a subject in need of the same. 12.Compounds of the formula Het-CHOH-CH₂ -NH₂ wherein Het has the formula##STR59## tautomers and individual enantiomers thereof.
 13. A method fortreating hypertension by administering a pharmaceutically effectiveanti-hypertensive amount of a composition of claim 10 in a suitabledosage form to a subject in need of such treatment.
 14. A method foreffecting bronchodilation by administering a pharmaceutically effectivebronchodilating amount of a composition of claim 10 in a suitable dosageform to a subject in need of such treatment.